ABSTRACT The goal of this proposal is to investigate possible contributions of Swedish mutant amyloid precursor protein (APPswe) in peripheral tissues (e,g, bone cells and muscles) to the pathogenesis of Alzheimer?s disease (AD). App is a mendelian gene for early-onset AD. Mutations in App (e.g., Swedish mutation) favor APP cleavage to generate A?40-42. Much research on AD has thus focused on the accumulation of A?40-42 in the brain, even though it is widely recognized that App and other AD risk genes are expressed not only in the brain, but also in periphery tissues, including bone cells and muscles. Here, we asked if altered APP metabolism in osteoblasts (OBs) and muscles is linked with AD pathogenesis. Examinations of bone and muscle structures in Tg2576, a well-characterized AD animal model that expresses APPswe (Swedish mutant APP) ubiquitously and develops some AD-relevant brain-pathologic deficits, revealed that animals display early-onset osteoporotic deficits and muscle-weakness months before any brain-pathologic defect that can be detected. In addition to Tg2576, we have generated a conditional transgenic mouse model capable of cell-type specific expression of APPswe in Cre-dependent manner. Selective expression of APPswe in OB-lineage cells [including bone marrow mesenchymal stem cells (BMSCs), OB progenitors, OBs, and osteocytes] by crossing floxed APPswe transgene with osteocalcin (Ocn) promoter driven Cre (TgAPPswe-OcnCre) recapitulated the osteoporotic defect in Tg2576 mouse model, indicating a cell autonomous role of APPswe in suppressing bone formation and bone homeostasis. Selective expression of APPswe in muscles by crossing floxed APPswe transgene with human skeletal ?-actin (HSA) promoter driven Cre (TgAPPswe-HSACre) reduced muscle-mass and compound muscle action potential (CMAP) and increased denervation at neural muscular junction (NMJ) in young adult age, demonstrating a cell autonomous role of APPswe in suppressing adult NMJ maintenance and accelerating skeletal muscle aging. Further characterizations of APPswe+ OB-lineage cells or muscles revealed impaired mitochondrial function, increased reactive oxygen species (ROS), reduced cell growth, and elevated expression of multiple inflammatory cytokines and growth factors, exhibiting features of cellular senescence. These observations thus led to the hypothesis that altered APP metabolism in OB-lineage cells/muscles results in their senescence, and thus accelerating brain aging and contributing to AD pathogenesis. We will test this hypothesis by the accomplishment of the following two specific aims. In Aim 1, we will investigate the potential contributions of APPswe in OB-lineage cells to AD pathogenesis and the underlying mechanisms. In Aim 2, we will investigate functions and mechanisms of muscle-APPswe in AD pathogenesis. It is our hope that results of the proposed research may reveal novel pathophysiological mechanisms of APPswe in AD pathogenesis. Such knowledge may facilitate the development of biomarkers and strategies for early diagnosis and therapies of AD.